Human schistosomiasis, caused by three main species of tissue invasive parasitic trematodes, currently affects over 207 million individuals and remains a significant cause of morbidity in developing countries. Vaccine development for this disease has been hampered by a poor understanding of the mechanisms involved in protective immunity in humans. Many field-based studies have defined a correlation between high serum concentrations of parasite-specific IgE and resistance to reinfection following curative chemotherapy. The protective effect(s) of IgE remain elusive and may include roles as diverse as direct killing of worms or in regulating immunity. Our preliminary data shows that expression of CD23, the low affinity IgE receptor (Fc5RII), on CD19+ B cells is strongly associated with a history of resistance against S. mansoni in a well- defined cohort of occupationally hyper-exposed Kenyan laborers. We propose to define the role of CD23+ B cells in schistosomiasis by characterizing the specific subsets of B cells that express CD23 and the immunological predictors of CD23 expression. These analyses will be done on circulating B cells and serum samples derived from our well-defined study group of Kenyan laborers using flow cytometry and bead technology. CD23-bound IgE must be cross-linked by antigen to induce B cell activation. Most compelling, there are several antigens synthesized by pathogens which cross-link IgE in a non-antigen specific manner, likely via the Fc region of the antibody, including IPSE/alpha-1, produced by schistosomes. Our preliminary analysis demonstrates that the mechanism by which IgE is cross-linked influences that pathway of B cell differentiation. Whereas antigen-specific CD23-bound IgE cross-linking appears to lead B cells along a pathway of differentiation, non-specific cross-linking reduces activation levels. We hypothesize that IgE has an immunoregulatory role in human schistosomiasis through CD23 expressed on B cells in the development and maintenance of immunity to schistosomes. We plan to determine the effect of differential cross-linking of CD23-bound IgE by schistosome antigens on B cell differentiation and activation using IgE derived from our study population and naove B cells from uninfected donors. We predict that these studies will broaden our knowledge of the potential roles of IgE in protective immunity to schistosomiasis and pave the way for future studies. PUBLIC HEALTH RELEVENCE: Schistosomiasis is a disease that affects 207 million people worldwide and is caused by parasitic flatworms that reside in blood vessels. There is no vaccine because we do not understand how the human immune system is able to kill worms. These studies will delve into the mechanisms involved in human host protection to promote the development of an effective vaccine.